Neurotransmitter receptors provide access to neuronal circuits for investigation of their biology, and potentially for therapeutic intervention. Peptides have effects on G-protein coupled receptors that are often relatively long lasting and they may have a modulatory role. These subtle effects may be relevant to the basis or treatment of mental illness. We are studying a family of G-protein coupled receptors (referred to as the secretin-VIP, B, or type II family) that is structurally distinct from the majority of G-protein coupled receptors (rhodopsin- or beta-adrenergic-like). Recently we have focused on the parathyroid hormone 2 (PTH2) receptor, which we identified in a screen for novel receptors expressed in the brain. Our initial studies of the human PTH2 receptor showed that it was activated by parathyroid hormone (PTH). Mapping the PTH2 receptor's anatomical distribution revealed expression within brain areas not normally exposed to circulating peptides, such as PTH. Furthermore, we found that PTH poorly activates the rat PTH2 receptor. Using selective activation of the PTH2 receptor as an assay we purified a previously unknown 39 amino acid peptide from bovine hypothalamus. This peptide, which we named tuberoinfundibular peptide of 39 residues (TIP39), activates PTH2 receptors from human, rat and zebrafish and does not activate PTH1 receptors. Both rat and zebrafish PTH2 receptors are much more effectively activated by TIP39 than PTH, supporting the suggestion that a TIP39 homologue is their natural ligand. We have mapped the neuroanatomical distribution of TIP39 synthesizing neurons and their projections to different brain areas. This has generated hypotheses about potential physiological functions of TIP39. We have found that PTH2-R synthesizing neurons use glutamate as a neurotransmitter. Together with the predominant localization of the PTH2R in nerve terminals this suggests that TIP39 modulates excitatory neurotransmission in specific circuits. We are testing hypotheses for the biological role (s) of TIP39 and the PTH2 receptor derived from detailed mapping of the receptor and peptides distributions. We have obtained data that supports a role for TIP39 and the PTH2 receptor in modulating pain perception and shown that it has similar effects to antidepressant and anxiolytic drugs in some animal behavior assays. We, and other investigators, also have preliminary data supporting a role for TIP39 and the PTH2 receptor in modulation of pituitary hormone release. We have found significant changes in TIP39 synthesis during postnatal development, that suggest it has a development role. We are attempting to develop mice with PTH2 receptor and TIP39 null phenotypes to aid in elucidating the function of this peptide-receptor system.